ABSTRACT
So far, the cholinergic hypothesis of Alzheimer's disease (AD) remains the fundamental explanation for the complex etiopathology of AD. However, therapeutics raising synaptic acetylcholine (Ach) or having cholinergic receptors agonistic activity had shown limited clinical efficacy, possibly, due to lacking capability to aggregate cholinergic receptors within the degenerated cholinergic neurons. Vitamin-B12 (B12) is an epigenetic modifier. It has a specific CNS transport system via the cubam receptors. The later enclose a cholinergic aggregator; agrin protein, suggesting that B12 administration may cause cholinergic receptors aggregation. Further, B12 involvement in homocysteine (Hcy) metabolism may restore blood brain barrier (BBB) integrity disrupted by elevated Hcy levels in AD. Here in, using a pharmacological model of cholinergic amnesia, three different B12 doses were compared to the standard of care; donepezil (DON) regarding cholinergic system modulation, and their effect on Hcy metabolic pathways. Further, AD-associated cerebro-vascular pathology was assessed by morphometric analyses of cerebro-vasculature morphology and ultrastructure using scanning and transmission electron-microscopes, respectively. Consequent effect on key AD-hallmarks and behavioral cognitive tests was also examined. The highest B12-tested dose (B12-HD) showed the greatest hippocampal cholinergic modulation with dose-dependent preferential upregulation of one cholinergic receptor over the other. Altered Hcy metabolism was proved to be a consequence of cholinergic disruption that was variably reversed by different B12 doses. In spite of equipotent effect of DON and B12-HD therapies in decreasing ß-amyloid synthesis, B12-HD-treated group revealed the greatest restoration of BBB integrity indicating superior capability of ß-amyloid clearance. Therefore, B12-HD therapy may represent a promising AD-modifying agent with extra-ability over conventional cholinergic modulators to aggregate cholinergic receptors.
